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497 results on '"Bunting, Kevin D"'

1. JMML tumor cells disrupt normal hematopoietic stem cells by imposing inflammatory stress through overproduction of IL-1β

Author

Yan, Yuhan, Dong, Lei, Chen, Chao, Bunting, Kevin D, Li, Qianjin, Stieglitz, Elliot, Loh, Mignon L, and Qu, Cheng-Kui

Subjects
Orphan Drug, Stem Cell Research - Nonembryonic - Non-Human, Cancer, Pediatric, Rare Diseases, Stem Cell Research, Regenerative Medicine, Stem Cell Research - Nonembryonic - Human, Transplantation, Pediatric Cancer, Hematology, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Animals, Bone Marrow, Hematopoietic Stem Cells, Humans, Inflammation, Interleukin-1beta, Leukemia, Myelomonocytic, Juvenile, Mice, Myeloproliferative Disorders, Receptors, Interleukin-1, Tumor Microenvironment
Abstract

Development of normal blood cells is often suppressed in juvenile myelomonocytic leukemia (JMML), a myeloproliferative neoplasm (MPN) of childhood, causing complications and impacting therapeutic outcomes. However, the mechanism underlying this phenomenon remains uncharacterized. To address this question, we induced the most common mutation identified in JMML (Ptpn11E76K) specifically in the myeloid lineage with hematopoietic stem cells (HSCs) spared. These mice uniformly developed a JMML-like MPN. Importantly, HSCs in the same bone marrow (BM) microenvironment were aberrantly activated and differentiated at the expense of self-renewal. As a result, HSCs lost quiescence and became exhausted. A similar result was observed in wild-type (WT) donor HSCs when co-transplanted with Ptpn11E76K/+ BM cells into WT mice. Co-culture testing demonstrated that JMML/MPN cells robustly accelerated differentiation in mouse and human normal hematopoietic stem/progenitor cells. Cytokine profiling revealed that Ptpn11E76K/+ MPN cells produced excessive IL-1β, but not IL-6, T NF-α, IFN-γ, IL-1α, or other inflammatory cytokines. Depletion of the IL-1β receptor effectively restored HSC quiescence, normalized their pool size, and rescued them from exhaustion in Ptpn11E76K/+/IL-1R-/- double mutant mice. These findings suggest IL-1β signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.

Published
2022

2. Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells.

Author

Metts, Jonathan, Bradley, Heath L, Wang, Zhengqi, Shah, Neil P, Kapur, Reuben, Arbiser, Jack L, and Bunting, Kevin D

Subjects
Cell Line, Tumor, Lysosomes, Mitochondria, Cytosol, Humans, Calcium, Reactive Oxygen Species, Imipramine, Antineoplastic Agents, Apoptosis, Gene Duplication, Tandem Repeat Sequences, STAT5 Transcription Factor, fms-Like Tyrosine Kinase 3, Leukemia, Myeloid, Acute, Cell Line, Tumor, Leukemia, Myeloid, Acute
Abstract

Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML.

Published
2017

3. Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

Author

Chatterjee, Anindya, Ghosh, Joydeep, Ramdas, Baskar, Mali, Raghuveer Singh, Martin, Holly, Kobayashi, Michihiro, Vemula, Sasidhar, Canela, Victor H, Waskow, Emily R, Visconte, Valeria, Tiu, Ramon V, Smith, Catherine C, Shah, Neil, Bunting, Kevin D, Boswell, H Scott, Liu, Yan, Chan, Rebecca J, and Kapur, Reuben

Subjects
Childhood Leukemia, Hematology, Cancer, Pediatric Cancer, Rare Diseases, Pediatric, Genetics, Aetiology, 2.1 Biological and endogenous factors, Animals, Benzothiazoles, Carcinogenesis, Cell Nucleus, Cell Proliferation, Focal Adhesion Protein-Tyrosine Kinases, Guanine Nucleotide Exchange Factors, Humans, Leukemia, Myeloid, Acute, Mastocytosis, Systemic, Mice, Inbred C57BL, Mutant Proteins, Mutation, Phenylurea Compounds, Phosphorylation, Protein Kinase Inhibitors, Protein Transport, Proto-Oncogene Proteins c-kit, STAT5 Transcription Factor, Signal Transduction, Survival Analysis, T-Lymphoma Invasion and Metastasis-inducing Protein 1, fms-Like Tyrosine Kinase 3, p21-Activated Kinases, rac1 GTP-Binding Protein, Biochemistry and Cell Biology, Medical Physiology
Abstract

Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

Published
2014

13. Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT

Author

Mali, Raghuveer Singh, Ma, Peilin, Zeng, Li-Fan, Martin, Holly, Ramdas, Baskar, He, Yantao, Sims, Emily, Nabinger, Sarah, Ghosh, Joydeep, Sharma, Namit, Munugalavadla, Veerendra, Chatterjee, Anindya, Li, Shuo, Sandusky, George, Craig, Andrew W., Bunting, Kevin D., Feng, Gen-Sheng, Chan, Rebecca J., Zhang, Zhong-Yin, and Kapur, Reuben

Published
2012
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30. Hematopoietic reconstitution with androgenetic and gynogenetic stem cells

Author

Eckardt, Sigrid, Leu, N. Adrian, Bradley, Heath L., Kato, Hiromi, Bunting, Kevin D., and McLaughlin, K. John

Subjects
Parthenogenesis -- Research, Transplantation of organs, tissues, etc. -- Research, Stem cell research, Biological sciences
Abstract

Uniparental fetal liver cells were transplanted into lethally irradiated adult mice to test their capacity to replace adult hematopoietic tissue. The evidence suggests that transplanted uniparental cells could proliferate in and even replace an adult organ substantiating the concept of using derivatives of uniparental embryonic stem cells for transplantation.

Published
2007

40. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype

Author

Zhou, Sheng, Schuetz, John D., Bunting, Kevin D., Colapietro, Anne-Marie, Sampath, Janardhan, Morris, John J., Lagutina, Irina, Grosveld, Gerard C., Osawa, Mitsujiro, Nakauchi, Hiromitsu, and Sorrentino, Brian P.

Abstract

Stem cells from bone marrow, skeletal muscle and possibly other tissues can be identified by the 'side-population' (SP) phenotype. Although it has been assumed that expression of ABC transporters is responsible for this phenotype, the specific molecules involved have not been defined. Here we show that expression of the Bcrp1 (also known as Abcg2 murine/ABCG2 human) gene is a conserved feature of stem cells from a wide variety of sources. Bcrp1 mRNA was expressed at high levels in primitive murine hematopoietic stem cells, and was sharply downregulated with differentiation. Enforced expression of the ABCG2 cDNA directly conferred the SP phenotype to bone-marrow cells and caused a reduction in maturing progeny both in vitro and in transplantation-based assays. These results show that expression of the Bcrp1/ABCG2 gene is an important determinant of the SP phenotype, and that it might serve as a marker for stem cells from various sources., Author(s): Sheng Zhou [1]; John D. Schuetz [2]; Kevin D. Bunting [1]; Anne-Marie Colapietro [1]; Janardhan Sampath [2]; John J. Morris [1]; Irina Lagutina [3]; Gerard C. Grosveld [3]; Mitsujiro [...]

Published
2001
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45. Stat5 tetramer formation is associated with leukemogenesis

Author

Moriggl, Richard, Sexl, Veronika, Kenner, Lukas, Duntsch, Christopher, Stangl, Katharina, Gingras, Sebastien, Hoffmeyer, Angelika, Bauer, Anton, Piekorz, Roland, Wang, Demin, Bunting, Kevin D., Wagner, Erwin F., Sonneck, Karoline, Valent, Peter, Ihle, James N., and Beug, Hartmut

Published
2005
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47. Stat5 expression is critical for mast cell development and survival

Author

Shelburne, Christopher P., McCoy, Margaret E., Piekorz, Roland, Sexl, Veronica, Roh, Kwan-Ho, Jacobs-Helber, Sarah M., Gillespie, Sheila R., Bailey, Daniel P., Mirmonsef, Paria, Mann, Meredith N., Kashyap, Mohit, Wright, Harry V., Chong, Hey Jin, Bouton, L. Andrew, Barnstein, Brian, Ramirez, Carlos D., Bunting, Kevin D., Sawyer, Steven, Lantz, Chris S., and Ryan, John J.

Published
2003
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49. Gab2 and Gab3 Redundantly Suppress Colitis by Modulating Macrophage and CD8+ T-Cell Activation

Author

Wang, Zhengqi, primary, Vaughan, Tamisha Y., additional, Zhu, Wandi, additional, Chen, Yuhong, additional, Fu, Guoping, additional, Medrzycki, Magdalena, additional, Nishio, Hikaru, additional, Bunting, Silvia T., additional, Hankey-Giblin, Pamela A., additional, Nusrat, Asma, additional, Parkos, Charles A., additional, Wang, Demin, additional, Wen, Renren, additional, and Bunting, Kevin D., additional

Published
2019
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